Glia and excitability in epilepsy and infantile spasm

Figure 1. Schematic model depicting selected interactions between astrocytes and excitatory neurons. Voltage-gated Na+ and K+ channels (1) generate action potentials in the presynaptic neuron, leading to the exocytotic synaptic release of neurotransmitter glutamate(2). Glutamate activates AMPA and NMDA receptors (3) in the postsynaptic membrane, causing excitatory synaptic potentials generated by influx of Na+ and Ca2+. If sufficiently strong, synaptic excitation leads to epileptiform discharges (4). Glutamate is taken up into reactive astrocytes by the EAAT1 (GLAST) and EAAT2 (GLT-1) transporters (5) and is converted to glutamine by glutamine synthetase (6). Glutamine is a substrate for the production of GABA in inhibitory GABAergic neurons (not shown). Loss of glutamine synthetase in reactive astrocytes leads to a decrease in GABA production. K+ released from neurons by voltage-gated (outwardly rectifying) K+ channels enters astrocytes via inwardly rectifying K+ channels (Kir4.1) (7) and is distributed into capillaries. Aquaporin-4 (AQP4) concentrated at astrocytic endfoot processes regulates water balance (8). Ca2+ waves (9) stimulate the release of gliotransmitters (10) that can influence neuronal excitability. The inhibitory substance adenosine is taken up into astrocytes by the equilibrative nucleoside transporters ENT1 and ENT2 and concentrative nucleoside transporter CNT2. Excessive adenosine kinase in reactive astrocytes increases the removal of adenosine (11), enhancing hyperexcitability.

Categories
1. AP  --> glutamate release --> AMPA/NMDA  --> Na, Ca influx
    ; epileptiform discharge, if strong

2. Glutamate uptake (EAAT1,2) in astrocyte --> glutamine --> GABA production by GS
    ; epileptiform discharge, if EAAT1,2 mutation, GS deficient

3. K release from neuron by voltage-gated K channel à inward K channel (Kir4.1) in astrocyte
   ; reduced Kir4.1 expression --> epileptogenesis

4. AQP4 distribution in astrocyte

5. Ca wave in astrocyte --> gliotransmitter release

6. Adenosine in astrocyte (uptaken by ENT1,2) --> enhanced adenosine kinase (ADK) --> AMP


Glia and epilepsy

1. Water and K+ buffering
   1.AQP4
   2.Kir4.1

2. Regulating Neurotransmission
  1.GLAST, GLT-1 (EAAT1, EAAT2)
  2.ADK
  3.GS

3. Gliotransmission
  1. Ca wave by G-protein-coupled recetor-induced increased PLC or cyclooxygenase-2 prostaglandin signaling
  2. D-serine
  3. GABA

4. Vasculature and BBB
  1. VEGF
  2. Albumin-mediated activation of TGFb
  3. p-glycoprotein

5. Glia-mediated immunity and inflammation



Table 1. Mechanisms of glia-mediated neuronal hyperexcitablity